The decline in GH secretion with age may play a major role in the increasing morbidity and frailty, and the reduced quality of life of the aging population. Recent studies by this group demonstrate that the decline in GH secretion can be reversed by taking a daily oral dose of the GHRP mimetic MK-677 and these results are compatible with the focus of this grant: the decline of GH secretion with age is mediated by decreased secretion of the natural ligand for GHRP. Diminished GHRP natural ligand production may decrease GHRH release, increase SRIH release and reduce the effectiveness of GHRH on somatotroph function. Decreased GH secretion likely promotes reduction of lean tissue (sarcopenia) and accumulation of abdominal (visceral) fat as occurs in GH deficient adults, resulting in insulin resistance and increased cardiovascular risk. Recent developments offer new possibilities to investigate the regulation of GH secretion. Both human and animal experiments are proposed to explore our central hypothesis. Specific Aim 1. Hypothesis: Long term administration (2 yr) of an oral GHRP mimetic (MK-677) in the elderly will restore GH secretion to that observed in young adults. The restoration of GH secretion will alter body composition, metabolic rate, aerobic exercise capacity, proximal muscle strength and bone density toward that of young adults. Specific Aim 2. Hypothesis: The decline of GH secretion with aging is mediated by a reduced hypothalamic stimulation of somatotrophs. Blockade of GH feedback with a GH receptor antagonist (opening the negative feedback loop) will augment GH secretion more in young than in older adults. Studies will be performed in young and older adults and in young and old rats. Specific Aim 3. Hypothesis: Enhanced SRIH secretion and/or action contributes to the decline of GH secretion with increasing age. Administration of the somatostatin receptor-2 (SSTR2) antagonist (to block the primary SRIH receptor subtype mediating inhibition of GH secretion) will lead to increased GH secretion. Increased SRIH secretion inhibits GH secretion directly and possibly indirectly by also decreasing GHRH release. The recent development of a SSTR2 antagonist now permits evaluation of the critical role of this receptor in pulsatile GH secretion in animals and man and will also allow determination of the relative role of SRIH in the regulation of GH secretion in the young versus the old. Specific Aim 4. Hypothesis: IGFBP-1 is pivotal in regulating IGF-1 feedback by modulating circulating free IGF-1 concentrations. IGFBP-1 inhibits IGF-1 action and circulation levels are correlated inversely with serum insulin concentrations. Since IGFBP-1 is low in older adults with increased visceral fat, administration of metformin, a biguanide, for 4 weeks will lower insulin levels without changing blood glucose, will increase circulating IGFBP1 levels and thus enhance GH secretion in older adults.